Adjuvants are compounds added to vaccine formulations to enhance antigen-specific immune responses in vaccine recipients. Modern vaccine development requires safe and effective adjuvants, but the adjuvants now available to vaccine producers pose problems for human use. The best-known adjuvants include alum, Freund's complete, and Freund's incomplete. Though it has a good safety record, alum stimulates weak antibody responses against protein antigens. O'Hagan et al., (2001) Biomolecular Engineering 18:69-85. Moreover, alum adjuvants can induce IgE antibody production and may prompt allergic responses in some recipients. Freund's complete adjuvant and its variants demonstrate promising immunostimulation but are not suitable for human use because they cause unacceptable necrosis and tissue damage. Aucouturier et al., (2001) Vaccine 19:2666-2671. Freund's incomplete adjuvant, though less toxic, presents similar safety risks.
Mast cells reside at the host's interface with the surrounding environment and carry out specialized immune functions. Mast cells carry abundant, specialized intracellular granules storing many pre-synthesized immune mediators such as TNF-α, histamine, and tryptase that can be rapidly released through a process known as degranulation. Marshall and Bienenstock, (1994) Curr Opin Immunol 6:853-9. Because they can undergo repeated cycles of degranulation and regranulation, mast cells are major mediators of immune stimulation and inflammation in the host. For example, mast cells have been implicated in several inflammatory disorders, including asthma, allergy, inflammatory bowel disease and arthritis, and have also been shown to have beneficial effects in promoting bacterial clearance through neutrophil recruitment to sites of bacterial infection. Malaviya et al., (1996) Nature 38:77-80; Echtenacher et al., (1996) Nature 381:75-7.
Chemical mast cell activators, such as compound 48/80 (C48/80), have been shown to mediate recruitment of immune cells to regional lymph nodes. Koibuchi, et al., (1985) European J. of Pharm. 115(2-3):171-177; Stanovnik, et al., (1988) Agents Actions 23(3-4):300-303; McLachlan, et al., (2008) Nat. Med. 14(5):536. In addition, C48/80 acts as an adjuvant for nasally administered vaccines with efficacy comparable to cholera toxin—the “gold standard” for mucosal vaccine adjuvant activity. McLachlan, et al., (2008) Nat. Med. 14(5):536.
Nevertheless, despite its experimental promise, C48/80 faces barriers that likely preclude its use in human vaccines. McLachlan et al., (2008) Nat. Med. 14(5):536; McGowen, et al., (2009) Vaccine 27(27):3544-3552. For example, C48/80 is a condensation product of N-methyl-p-methoxyphenethylamine with formaldehyde (see, e.g., SIGMA, Cat. # C2313) and represents an uncharacterized mixture of polymer species. Koibuchi, et al., (1985) European J. of Pharm. 115(2-3):171-177. The use of C48/80 in humans would likely require the difficult task of identifying the single species mediating adjuvant activity, if such a single species even exists.
Thus, there is a need for improved and alternative mast cell activating compounds, adjuvant compositions, and vaccine compositions that can induce improved immune responses in a mammalian subject.